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Cyclosporine A impairs nucleotide binding oligomerization domain (Nod1)-mediated innate antibacterial renal defenses in mice and human transplant recipients.

ABSTRACT: Acute pyelonephritis (APN), which is mainly caused by uropathogenic Escherichia coli (UPEC), is the most common bacterial complication in renal transplant recipients receiving immunosuppressive treatment. However, it remains unclear how immunosuppressive drugs, such as the calcineurin inhibitor cyclosporine A (CsA), decrease renal resistance to UPEC. Here, we investigated the effects of CsA in host defense against UPEC in an experimental model of APN. We show that CsA-treated mice exhibit impaired production of the chemoattractant chemokines CXCL2 and CXCL1, decreased intrarenal recruitment of neutrophils, and greater susceptibility to UPEC than vehicle-treated mice. Strikingly, renal expression of Toll-like receptor 4 (Tlr4) and nucleotide-binding oligomerization domain 1 (Nod1), neutrophil migration capacity, and phagocytic killing of E. coli were significantly reduced in CsA-treated mice. CsA inhibited lipopolysaccharide (LPS)-induced, Tlr4-mediated production of CXCL2 by epithelial collecting duct cells. In addition, CsA markedly inhibited Nod1 expression in neutrophils, macrophages, and renal dendritic cells. CsA, acting through inhibition of the nuclear factor of activated T-cells (NFATs), also markedly downregulated Nod1 in neutrophils and macrophages. Silencing the NFATc1 isoform mRNA, similar to CsA, downregulated Nod1 expression in macrophages, and administration of the 11R-VIVIT peptide inhibitor of NFATs to mice also reduced neutrophil bacterial phagocytosis and renal resistance to UPEC. Conversely, synthetic Nod1 stimulating agonists given to CsA-treated mice significantly increased renal resistance to UPEC. Renal transplant recipients receiving CsA exhibited similar decrease in NOD1 expression and neutrophil phagocytosis of E. coli. The findings suggest that such mechanism of NFATc1-dependent inhibition of Nod1-mediated innate immune response together with the decrease in Tlr4-mediated production of chemoattractant chemokines caused by CsA may contribute to sensitizing kidney grafts to APN.

SUBMITTER: Tourneur E

PROVIDER: S-EPMC3561241 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Cyclosporine A impairs nucleotide binding oligomerization domain (Nod1)-mediated innate antibacterial renal defenses in mice and human transplant recipients.

Tourneur Emilie E Ben Mkaddem Sanae S Chassin Cécilia C Bens Marcelle M Goujon Jean-Michel JM Charles Nicolas N Pellefigues Christophe C Aloulou Meryem M Hertig Alexandre A Monteiro Renato C RC Girardin Stephen E SE Philpott Dana J DJ Rondeau Eric E Elbim Carole C Werts Catherine C Vandewalle Alain A

PLoS pathogens 20130131 1

Acute pyelonephritis (APN), which is mainly caused by uropathogenic Escherichia coli (UPEC), is the most common bacterial complication in renal transplant recipients receiving immunosuppressive treatment. However, it remains unclear how immunosuppressive drugs, such as the calcineurin inhibitor cyclosporine A (CsA), decrease renal resistance to UPEC. Here, we investigated the effects of CsA in host defense against UPEC in an experimental model of APN. We show that CsA-treated mice exhibit impair ...[more]

PMID: 23382681

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Project description:Apixaban is frequently used off-label in transplant recipients. However, a potential drug interaction exists with the calcineurin inhibitors. We conducted an open-label drug-drug interaction study to determine the pharmacokinetics of apixaban in lung and kidney transplant recipients who were taking a calcineurin inhibitor. A single dose of apixaban 10 mg was administered orally to kidney and lung transplant recipients maintained on either tacrolimus or cyclosporine, and pharmacokinetic parameters were compared to a reference cohort of 12 healthy subjects who used the same apixaban dose and pharmacokinetic blood sampling. Fourteen participants were enrolled (n = 6 kidney, n = 8 lung), with 10 maintained on tacrolimus and four on cyclosporine. Data from 13 participants was usable. Participants were taking triple therapy immunosuppression and had a mean (SD) of 12 (3) medications. Participants receiving tacrolimus and cyclosporine had area under the plasma concentration-time curve from time zero to infinity (AUC0-inf ) geometric least square means (90% confidence interval [CI]) of 4312 (95% CI 3682, 5049) and 5388 (95% CI 3277, 8858), respectively. Compared to healthy subjects, the associated geometric mean ratios (GMRs) for apixaban maximum plasma concentration (Cmax ), AUC from time zero to the last quantifiable concentration (AUC0-tlast ) and AUC0-inf were 197% (95% CI 153, 295), 244% (95% CI 184, 323), and 224% (95% CI 170, 295) for transplant recipients on tacrolimus. The GMR (90% CI) Cmax , AUC0-tlast , and AUC0-inf of apixaban for patients on cyclosporine were 256% (95% CI 184, 358), 287% (95% CI 198, 415), and 280% (95% CI 195, 401). Kidney and lung transplant recipients receiving tacrolimus had higher apixaban exposure. A similar trend was noted for patients receiving cyclosporine, but additional patients are needed to confirm this interaction. Future studies are needed before apixaban can be safely recommended in this population, and the impact of dose staggering should be investigated. This study highlights the importance of pharmacokinetic studies in actual patient populations.

Project description:BACKGROUND:Calcineurin-inhibitors and hepatitis C virus (HCV) infection increase the risk of post-transplant diabetes mellitus. Chronic HCV infection promotes insulin resistance rather than beta-cell dysfunction. The objective was to elucidate whether a conversion from tacrolimus to cyclosporine A affects fasting and/or dynamic insulin sensitivity, insulin secretion or all in HCV-positive renal transplant recipients. METHODS:In this prospective, single-center study 10 HCV-positive renal transplant recipients underwent 2h-75g-oral glucose tolerance tests before and three months after the conversion of immunosuppression from tacrolimus to cyclosporine A. Established oral glucose tolerance test-based parameters of fasting and dynamic insulin sensitivity and insulin secretion were calculated. Data are expressed as median (IQR). RESULTS:After conversion, both fasting and challenged glucose levels decreased significantly. This was mainly attributable to a significant amelioration of post-prandial dynamic glucose sensitivity as measured by the oral glucose sensitivity-index OGIS [422.17 (370.82-441.92) vs. 468.80 (414.27-488.57) mL/min/m2, p = 0.005), which also resulted in significant improvements of the disposition index (p = 0.017) and adaptation index (p = 0.017) as markers of overall glucose tolerance and beta-cell function. Fasting insulin sensitivity (p = 0.721), insulinogenic index as marker of first-phase insulin secretion [0.064 (0.032-0.106) vs. 0.083 (0.054-0.144) nmol/mmol, p = 0.093) and hepatic insulin extraction (p = 0.646) remained unaltered. No changes of plasma HCV-RNA levels (p = 0.285) or liver stiffness (hepatic fibrosis and necroinflammation, p = 0.463) were observed after the conversion of immunosuppression. CONCLUSIONS:HCV-positive renal transplant recipients show significantly improved glucose-stimulated insulin sensitivity and overall glucose tolerance after conversion from tacrolimus to cyclosporine A. Considering the HCV-induced insulin resistance, HCV-positive renal transplant recipients may benefit from a cyclosporine A-based immunosuppressive regimen. TRIAL REGISTRATION:ClinicalTrials.gov NCT02108301.

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Cyclosporine A impairs nucleotide binding oligomerization domain (Nod1)-mediated innate antibacterial renal defenses in mice and human transplant recipients.

Publications

Cyclosporine A impairs nucleotide binding oligomerization domain (Nod1)-mediated innate antibacterial renal defenses in mice and human transplant recipients.

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